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Reactions of Alcohols

Reactions of Alcohols. oxidation tosylation and reactions of tosylates substitutions to form alkyl halides dehydration to form alkenes and ethers pinacol rearrangement esterification cleavage of glycols ether synthesis. Classification of Reactions. Oxidations addition of O or O 2

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Reactions of Alcohols

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  1. Reactions of Alcohols • oxidation • tosylation and reactions of tosylates • substitutions to form alkyl halides • dehydration to form alkenes and ethers • pinacol rearrangement • esterification • cleavage of glycols • ether synthesis

  2. Classification of Reactions • Oxidations • addition of O or O2 • addition of X2 • loss of H2 • Reductions • loss of O or O2 • loss of X2 • addition of H2 or H-

  3. Classification of Reactions • Neither an oxidation nor a reduction • Addition or loss of H+ • Addition or loss of OH- • Addition or loss of H2O • Addition or loss of HX

  4. Classification of Reactions • Oxidations • count C-O bonds on a single C • the more C-O bonds, the more oxidized the C increasing level of oxidation

  5. Reactions of Alcohols - Oxidation • For alcohols, the oxidation comes from the loss of H2. • Oxidation of a 2° alcohol gives a ketone. • Chromic acid reagent used in lab oxidations. • Na2Cr2O7 + H2SO4 + H2O  2H2CrO4 + 2NaHSO4 • CrO3 + H2O (dil H2SO4)  H2CrO4

  6. Reactions of Alcohols - Oxidation • Oxidation of a 1° alcohol gives • a carboxylic acid if chromic acid reagent is used. • an aldehyde if pyridinium chlorochromate (PCC) is used.

  7. Reactions of Alcohols - Oxidation • Two other reagents behave like the chromic acid reagent: • KMnO4 (will attack C=C, too) • HNO3 • These two oxidizing agents are so strong that C-C bonds may be cleaved. • Bleach (OCl-) also oxidizes alcohols.

  8. Reactions of Alcohols – Swern Oxidation • Uses dimethyl sulfoxide (DMSO), oxalyl chloride (COCl)2 and a hindered base. • The reactive species is (CH3)2SCl+. • The result is a ketone or an aldehyde (the same as for PCC).

  9. Reactions of Alcohols – Swern Oxidation • Uses dimethyl sulfoxide (DMSO), oxalyl chloride (COCl)2 and a hindered base.

  10. Reactions of Alcohols – Oxidation with DMP • Uses Dess-Martin periodinane (DMP). • Mild conditions: room temperature and neutral pH with excellent yields • The result is a ketone or an aldehyde (the same as for PCC and the Swern oxidation).

  11. Reactions of Alcohols – Oxidation with DMP • Uses Dess-Martin periodinane (DMP).

  12. Reactions of Alcohols - Biological Oxidation • Ethanol is the least toxic alcohol, but it is still toxic. • The body detoxifies ethanol with NAD catalyzed first by alcohol dehydrogenase (ADH) and second by aldehyde dehydrogenase (ALDH): • ethanol  acetic acid • The reason methanol and ethylene glycol are so toxic to humans is that, when they react with NAD/ADH/ALDH, the products are more toxic than the original alcohols. • methanol  formic acid • ethylene glycol  oxalic acid

  13. Reactions of Alcohols - Oxidation • 3° alcohols will not oxidize, because there is no H on the carbinol C atom. • The chromic acid test capitalizes on this fact: • orange chromic acid reagent turns green or blue (due to Cr3+) in the presence of 1° or 2° alcohols, but doesn’t change color in the presence of a 3° alcohol.

  14. Reactions of Alcohols - Tosylation • In order to perform an SN2 reaction on an alcohol, i.e., with the alcohol as the substrate, the -OH group must leave the alcohol: • R-OH + Nuc:- R-Nuc + OH- • OH- is a poor leaving group • H2O is a better leaving group, but this requires protonation of the alcohol which, in turn, requires an acidic solution. Most nucleophiles are strong bases and cannot exist in acidic solutions. • We need to convert the alcohol to an electrophile that is compatible with basic nucleophiles.

  15. Reactions of Alcohols - Tosylation • Converting the alcohol to an alkyl halide (already discussed) or an alkyl tosylate lets it act as an electrophile. Stereochemical configuration of alcohol is retained.

  16. A Tosylate Ion is an EXCELLENT LEAVING GROUP • As good as or better than a halide.

  17. A Tosylate Ion is an EXCELLENT LEAVING GROUP • As such, tosylates (just like halides) are candidates for • SN2 reactions • E2 reactions • SN1 reactions • E1 reactions • Just like the halides

  18. SN2 Reactions of Tosylates • R-OTs + OH- ROH (alcohol) + -OTs • R-OTs + CN- RCN (nitrile) + -OTs • R-OTs + Br- RBr (alkyl halide) + -OTs • R-OTs + R’O- ROR’ (ether) + -OTs • R-OTs + NH3 RNH3+-OTs (amine salt) • R-OTs + LiAlH4 RH (alkane) + -OTs

  19. SN2 Reactions of Tosylates - Mechanism • Single step • Inversion of configuration

  20. Alcohols to Alkyl Halides: Hydrohalic Acids (HX) • Hydrohalic acids are strong acids, existing in aqueous solution as H+ and X-. • Recognize a hydrohalic acid: NaBr/H2SO4 • The H+ is need to convert the -OH of the alcohol into a good leaving group (H2O). The reaction mechanism, SN1 or SN2, depends on the structure of the alcohol.

  21. Alcohols to Alkyl Halides: Hydrohalic Acids (HX) • The structure of the alcohol dictates whether the mechanism is SN1 or SN2.

  22. Alcohols to Alkyl Chlorides: The Lucas Reagent • Cl- is a weaker nucleophile than Br-. • ZnCl2 coordinates with the -OH of the alcohol (like H+ does) to form a better leaving group (HOZnCl2-) than water. • ZnCl2 is a better Lewis acid than H+. • This promotes the SN2 reaction between HCl and 1° and 2° alcohols. • HCl/ZnCl2 is called the Lucas reagent.

  23. Alcohols to Alkyl Chlorides: The Lucas Test • Add the Lucas reagent to a solution of the unknown alcohol and time the formation of a second phase. • 3° alcohols react immediately. • 2° alcohols take 1-5 minutes. • 1° alcohols take >6 minutes.

  24. Alcohols to Alkyl Halides: Limitations of Using HX • This reaction does not always give good yields of RX. • 1° and 2° alcohols react slowly with HCl, even with ZnCl2 added. • Heating an alcohol with HCl or HBr can give the elimination product, an alkene. • Rearrangements can occur with SN1 (this is not necessarily bad). • HI does not give good yields of alkyl iodides, a valuable class of reagents.

  25. Alcohols to Alkyl Halides: PBr3 and P/I2 • Can give good yields of 1° and 2° alkyl bromides and iodides without the acidic conditions that go with HX. • 3 R-OH + PBr3 3RBr + P(OH)3 • PI3 is unstable and must be made in situ: • 6 R-OH + 2P + 3I2  6RI + 2P(OH)3 • PBr3 and P/I2 do NOT work well with 3° alcohols.

  26. Alcohols to Alkyl Halides: PBr3 Mechanism A double SN2 mechanism, which is why it does not work on 3° alcohols. Inversion of configuration, but no rearrangements.

  27. Alcohols to Alkyl Halides: Thionyl Chloride, SOCl2 • Often the best way to make an alkyl chloride from an alcohol. ROH + SOCl2 RCl + HCl(g) + SO2(g) • Gaseous by-products keep the equilibrium well to the right. heat dioxane

  28. Alcohols to Alkyl Halides: Best Reagents

  29. Alcohols to Alkenes: Acid-Catalyzed Dehydration • We studied this in the formation of alkenes. • E1 elimination of a protonated alcohol • Best for 3° and 2° alcohols • Rearrangements common for 1° alcohols due to the carbocation intermediate • Zaitsev product predominates.

  30. Alcohols to Alkenes: Acid-Catalyzed Dehydration • Step 1: protonation of the alcohol • Fast equilibrium • Converts OH to a good leaving group

  31. Alcohols to Alkenes: Acid-Catalyzed Dehydration • Step 2: ionization to a carbocation • slow, rate-limiting • leaving group is H2O

  32. Alcohols to Alkenes: Acid-Catalyzed Dehydration • Step 3: deprotonation to give alkene • fast • The carbocation is a strong acid: a weak base like water or bisulfate can abstract the proton.

  33. Alcohols to Symmetric Ethers: Bimolecular Dehydration • Competes with alkene formation. • Lower temperatures favor ether formation, a ΔS thing. • After protonation, the alcohol can undergo an SN2 attack by another alcohol molecule to form a symmetric ether.

  34. 3° Vicinal Diols to Ketones: The Pinacol Rearrangement • Acid-catalyzed dehydration of a 3° vicinal diol to form a ketone. • Involves a methyl migration, ~CH3

  35. 3° Vicinal Diols to Ketones: The Pinacol Rearrangement 3° carbocation resonance-stabilizedcarbocation

  36. 3° Vicinal Diols to Ketones: The Pinacol Rearrangement

  37. Vicinal Diols to Carbonyls: Periodic Acid Cleavage of Glycols • Periodic acid is HIO4. • Products are aldehydes and ketones. • Products the same as for ozonolysis. HIO4

  38. Alcohols to Esters: Acids • When the acid is a carboxylic acid, the reaction is called Fischer esterification. • This is an equilibrium, and it does not always favor the ester.

  39. Alcohols to Esters: Acids • When the acid is sulfuric acid, the product is a sulfate ester.

  40. Alcohols to Esters: Acids • When the acid is nitric, and propane-1,2,3-triol (glycerine) is the alcohol, what is the product? • When the acid is phosphoric acid, the product is a phosphate ester. • Phosphate esters are the links between nucleotides in RNA and DNA.

  41. DNA image from Wikipedia

  42. Oxidation or Reduction?

  43. Predict the Product

  44. Predict the Product

  45. Predict the Product As opposed to 180°C.

  46. Predict the Product

  47. Conversions

  48. Conversions

  49. Conversions

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